HLA-DR-Expressing γδ T Cells Facilitate the Anti-Leukemia Activity of αβ T Cells

In addition to exhibiting significant cytotoxic capabilities, γδ T cells play a crucial role as a bridge between innate and adaptive immunity. Although γδ T cells have been demonstrated to orchestrate interactions with other immune cells, their impact on αβ T cells in the setting of acute myeloid leukemia (AML) remains unexplored. In this study, we found that functional deficiencies of αβ T cells were significantly associated with the downregulation of HLA-DR⁺ γδ T cells in patients newly diagnosed with AML. Vδ2⁺ T cells, which constitute a predominant subset of γδ T cells in human peripheral blood, exhibited elevated levels of HLA-DR following ex vivo expansion. Notably, a lower dose of the expanded Vδ2⁺ T cells did not induce direct cytotoxicity against AML cells; instead, they significantly enhanced the cytotoxic capacity of primary αβ T cells toward AML cells. Furthermore, blockade of HLA-DR on Vδ2⁺ T cells markedly diminished this facilitating effect. Taken together, our findings demonstrate an important indirect role for Vδ2⁺ T cells beyond their direct killing ability in the context of anti-AML immunity and provide novel insights into the therapeutic potential of adoptive Vδ2⁺ T cell therapy.